Antisecretory imidazole amidine compounds, composition and method of use

ABSTRACT

Novel heterocyclic compounds shown by the formula ##STR1## wherein Het represents a 5-membered or 6-membered heterocyclic group which may have substituent(s); Z represents a sulfur atom or oxygen atom; X represents an oxygen atom or the unsubstituted or substituted imino group shown by N--R 1  (wherein R 1  is a hydrogen atom, a lower alkyl group, a cyano group, an unsubstituted or alkyl substituted carbamoyl group, an unsubstituted or lower alkyl substituted thiocarbamoyl group, or a lower alkanoylamino group); Y represents a hydrogen atom, a lower alkyl group which may have substituent(s), a cycloalkyl group of 3-6 carbon atoms, a lower alkenyl group, a lower alkynyl group, an aryl group which may have substituent(s), an aralkyl group which may have substituent(s), a hydroxyl group, a cyano group, a carbamoyl group, an amidino group, an alkanoyl group which may have been substituted by halogen atom(s), an alkanoylamino group, an arylcarbonylamino group, an alkylamino group, an arylamino group, an arylsulfamoyl group, a lower alkoxycarbamoyl group, or an oxamoylamino group; and m and n represent an integer of 1-3; when X is N--R 1 , said X and Y may combine with each other to form a 5-membered or 6-membered heterocyclic ring containing 2-3 nitrogen atoms which may have substituent(s), and the pharmacologically acceptable acid addition salts thereof. 
     The compounds of this invention are useful as gastric acid secretion inhibitors.

CROSS-REFERENCE TO RELATED APPLICATION

This application is a continuation-in-part of copending U.S. applicationSer. No. 934,276, filed Aug. 16, 1978, now U.S. Pat. No. 4,252,819.

DETAILED DESCRIPTION OF THE INVENTION

The present invention relates to novel heterocyclic compounds useful asgastric acid secretion inhibitors, the processes of producing them, andthe medical compositions containing them.

Thus, according to this invention, there are provided novel heterocycliccompounds represented by the general formula I ##STR2## wherein Hetrepresents a 5-membered or 6-membered heterocyclic group which may havesubstituent(s); Z represents a sulfur atom or an oxygen atom; Xrepresents an oxygen atom or the unsubstituted or substituted groupshown by the formula N--R₁ (wherein R₁ represents a hydrogen atom, alower alkyl group, a cyano group, an unsubstituted or loweralkyl-substituted carbamoyl group, an unsubstituted or loweralkyl-substituted thiocarbamoyl group, or a lower alkanoylamino group);Y represents a hydrogen atom, a lower alkyl group which may havesubstituent(s), a cycloalkyl group of 3-6 carbon atoms, a lower alkenylgroup, a lower alkynyl group, an aryl group which may havesubstituent(s), an aralkyl group which may have substituent(s), ahydroxyl group, a cyano group, a carbamoyl group, an amidino group, analkanoyl group which is substitutable by halogen atom(s), analkanoylamino group, an arylcarbonylamino group, an alkylamino group, anarylamino group, an arylsulfamoyl group, a lower alkoxycarbamoyl group,or an oxamoylamino group; and m and n each represents an integer of 1-3;when X is N--R₁, said X and Y may combine with each other to form a5-membered or 6-membered heterocyclic ring containing 2-3 nitrogen atomswhich may have substituent(s), and the acid addition salts of theheterocyclic compounds capable being supplied for medical purposes.

Furthermore, according to other embodiments of this invention, there areprovided a process of producing the novel heterocyclic compounds ofgeneral formula I and the medical compositions containing the novelheterocyclic compounds.

Now, in general formula I shown above, Het is a 5-membered or 6-memberedheterocyclic group which may have substituent(s) and practical examplesof such a heterocyclic group are isothiazolyl group, imidazolyl group,pyrazolyl group, thiazolyl group, pyrrolyl group, pyridazinyl group,pyrimidinyl group, pyrazinyl group, pyridyl group, triazolyl group,furyl group, and thienyl group. Also, the heterocyclic group may havesubstituent(s) and examples of such a substituent are, for example, ahalogen atom, hydroxyl group, lower alkyl group, lower alkoxy group,hydroxymethyl group, phenyl group, benzyl group, cyano group, aminogroup, aminoalkyl group, amidino alkyl group, etc. Also, the term"lower" in the explanation of the aforesaid general formula means astraight or branched carbon chain having 1-5 carbon atoms. Therefore, asa lower alkyl group, there are the methyl group, ethyl group, isopropylgroup, butyl group, etc.; as a lower alkenyl group, there are the vinylgroup, allyl group, isopropenyl group, etc.; as a lower alkynyl group,there are the ethynyl group, 2-propynyl group, 4-pentynyl group, etc.;and as a lower alkanoylamino group, there are the acetylamino group,propionylamino group, isobutyrylamino group, etc. Also, as the aralkylgroup, there are the benzyl group, pyridylmethyl group, etc. Moreover,these lower alkyl groups, aryl groups, and aralkyl groups may havesubstituent(s) such as, for example, the hydroxyl group, amino group,halogen atom, etc.

Then, X and Y in the general formula may combine with each other to forma heterocyclic group such as, for example, 1,2,4-oxadiazol-3-yl group,1,2,4-triazol-3-yl group, 1,3,5-triazine-2-yl group, pyrimidine-2-ylgroup, dihydropyridine-2-yl group, tetrahydropyrimidine-2-yl group,imidazol-2-yl group, etc., and these heterocyclic rings may further havesubstituent(s) such as, for example, the amino group, hydroxyl group,oxo group, lower alkyl group, halogen atom, lower alkoxycarbonyl group,carbamoyl group, etc.

Furthermore, the compounds of the aforesaid general formula I easilyform acid addition salts thereof and there also exist the tautomers ofthese compounds. Therefore, the invention includes also these acidaddition salts and the tautomers of the heterocyclic compounds ofgeneral formula I.

As mentioned above, the heterocyclic compounds of this invention readilyform acid addition salts capable of being used for medical purposes. Asthese salts, there are the salts of the heterocyclic compounds withinorganic acids and organic acids. Examples of the inorganic acid saltsare, for example, hydrochlorides, hydrobromides, and sulfates. Also,examples of the particularly useful organic acid salts are the saltswith aliphatic carboxylic acids such as acetic acid, maleic acid, andfumaric acid.

It is the first feature of this invention that the compounds provided bythis invention as characterized by a gastric acid inhibitory activityand this activity is not caused by an anticholinergic activity. Sinceconventional commercially available gastric acid secretion inhibitorsare mostly based on the anticholinergic activity and unwanted sideeffects caused by the anticholinergic activity have been pointed out,the compounds of this invention are useful as new type gastric acidsecretion inhibitors.

It is the second feature of this invention that some of the compounds ofthis invention have an activity for inhibiting gastric acid secretionthrough a histamine H₂ -receptor.

It has been proposed to classify histamine receptors into H₁ -receptorsand non H₁ -receptors or H₂ -receptors by Ash and Schild; "Brit. J. ofPharmacol. Chemother", 27, 427(1966) and Black et al.; "Nature", 236,385(1972). The effects of histamine on gastric acid secretion and heartrate in the Guinea pig isolated atrium is mediated by the H₂ -receptorand these effects are not inhibited by conventional antihistamines suchas mepyramine but are antagonized by blockers of H₂ -receptors such asmetiamide.

Since a histamine H₂ -receptor blocking agent inhibits the basicsecretion of gastric acid and the gastric acid secretion induced bygastrin or by food, it can be used for the treatment of gastric ulcerand duodenal ulcer caused by the hypersecretion of gastric acid.

Although the materials possessing the features as in the compounds ofthis invention, 2-phenyl-2-(2-pyridyl)-thioacetamide (Cook & Bianchi;"Life Sci."; 6, 1381(1967)) the compounds in Belgian Pat. Nos. 779,775;804,145; 857,388; etc., are known, the compounds of this inventionhowever are all novel compounds having different structures from theknown compounds.

The compounds of this invention can be administered orally orparenterally but the oral administration is preferred. The compounds ofthis invention are used as the free bases or the pharmacologicallyacceptable salts thereof and, in general, they are used as medical orpharmaceutical compositions with carriers or diluents which can be usedgenerally for preparing medicaments. In the case of oral administration,it is most convenient to use the medical compositions of this inventionin the form of capsules or tablets but they may be used as suspendedrelease preparations. Furthermore, the compositions may be used assugar-coated preparations or syrups. The doses thereof at oraladministration are 0.4 to 1 g. per day and it is proper to administerthe medicament in 1 to 4 divided doses.

The compounds of this invention shown by general formula I areinhibitors for gastric acid secretion induced by histamine, which willbe proved by the following tests:

(i) Effect of test compounds on gastric acid secretion inpylorus-ligated rats

Rats weighing about 200 g. were deprived of food for 24 hours and theirpylorus was ligated after an abdominal incision under ether anesthesia(Shay, H. et al.: Gastroenterol., 5, 43, 1945). Test compounds wereintraduodenally given immediately after the pylorus ligation. Theanimals were sacrificed 4 hours after drug administration and gastriccontents were collected. The gastric juice was titrated with 0.05 N NaOHto pH 7.0 for measurement of acidity.

As shown in table 1, the compounds reduced significantly the volume ofgastric juice and acid secretion.

                  TABLE 1                                                         ______________________________________                                        Effect of test compounds on gastric acid                                      secretion in pylorus-ligated rats                                             Dose                Gastric contents                                                  mg/kg;  No. of  Volume    Acid output                                 Compound                                                                              id      animals ml/4 hours/rat                                                                          μEq/4 hours/rat                          ______________________________________                                        Control --      7       3.2 ± 0.3                                                                            380 ± 40.1                               Example 44                                                                            50      7       1.4 ± 0.2*                                                                            79 ± 9.0*                               Example 41                                                                            50      7       1.5 ± 0.2*                                                                            97 ± 17.2*                              Example 42                                                                            50      7       1.7 ± 0.3*                                                                           137 ± 31.5*                              ______________________________________                                         id: intraduodenal administration,                                             Values represent mean ± S.E.                                               *p < 0.01                                                                

(ii) Histamine H₂ -receptor blocking activity of test compounds inisolated guinea-pig atria

Atrial preparations isolated from guinea-pigs were suspended inKrebs-Henseleit solution at 36° C. (Mitchell, I. et al. Europ. J.Pharmacol., 34, 95, 1975). The dose producing a 50% blockade ofchronotropic action of 5×10⁻⁶ M histamine was obtained from thedose-respose curve in which the inhibition percentage was plottedsemilogarithmically against dose.

As shown in Table 2, the compounds inhibited histamine-inducedtachycardia in isolated atrial preparations.

                  TABLE 2                                                         ______________________________________                                        Antagonistic activity of test compounds                                       on histamine-induced tachycardia in isolated                                  atria of guinea-pigs                                                          Compound     ED.sub.50, M                                                     ______________________________________                                        Example 44   (0.9 ± 0.1) × 10.sup.-6                                 Example 40   (2.3 ± 0.4) × 10.sup.-6                                 Example 41   (2.1 ± 0.2) × 10.sup.-6                                 ______________________________________                                         Values represent mean ± S.E. from 5 experiments.                      

The heterocyclic compounds of this invention shown by general formula Ican be produced by the following process:

Production process 1 ##STR3## in the formulae, R₂ represents a loweralkyl group and Het, X, Y, Z, m and n have the same significance asabove.

This process is performed by reacting the starting compound of formulaII₁ and a reactive amount of the amine of formula III. Examples of theamine shown by formula III used in the process are, for example,ammonia; a lower alkylamine such as methylamine, ethylamine,trifluoroethylamine, etc.; a cycloalkylamine such as cyclopropylamine,etc.; a lower alkenylamine such as allylamine, etc.; a loweralkynylamine such as 2-propynylamine, etc,; an aralkylamine such asbenzylamine, pyridylmethylamine, etc.; an aromatic amine such asaniline, etc,; a hydrazine such as hydrazine, acetylhydrazine,benzoylhydrazine, α-picolinylhydrazine, benzenesulfonylhydrazine,oxamoylhydrazine, alkyl-, aryl- or aralkyl-substituted hydrazine, etc.;an amidine such as formamidine, acetamidine, propionamidine, etc.;glycine, β-alanine or the esters of them; aminomalonic acid diester,aminoacetaldehyde diacetal, etc,; 3-aminoacrylic acid ester; urea;guanidine; cyanamide; and the like.

The reaction is usually performed in a solvent and suitable solvents,include alcohol, isopropanol, chloroform, ether, tetrahydrofuran,benzene, etc. It is preferred that these solvents do not contain water.There is no particular restriction about the reaction temperature butthe reaction is preferably performed at room temperature or underheating. Also, it is preferred that the reaction system is in a neutralto basic state.

In the reaction, depending on the group or element represented by X inthe starting compound of formula II₁ and the kind of the amine offormula III to be reacted therewith, X and Y of the heterocycliccompound of formula I may, as the case may be, combine with each otherto form a 5-membered or 6-membered ring in the objective compound. Forexample, there are the case of reacting the compound of formula II₁wherein X is an imino group (═NH) and a hydrazine compound such asacetylhydrazine, benzoylhydrazine, etc.; aminomalonic acid diester;glycine ester; aminoacetaldehyde dialkylacetal (e.g., H₂ NCH₂ CH(OC₂H₅)₂); 3-acrylic acid ester (e.g., H₂ N--CH═CHCOOC₂ H₃) etc., the caseof reacting the compound of formula II₁ wherein X is a cyanoimino group(═N--CN) and a hydrazine, a hydroxylamine, or an amidine, and the caseof reacting the compound of formula II₁ wherein X is a loweralcanoylaimino group (═N--CO-lower alkyl) and an amidine.

In these cases, the cyclized desired product of this invention may beobtained directly by the reaction of the raw material compound offormula II₁ and the amine of formula III but the cyclized objectivecompound of this invention may be prepared stepwise by forming once theuncyclized desired product of this invention shown by formula I and thencontinuing the reaction in situ or by changing the reaction conditions.

Production Process 2 ##STR4## in the formulae, Het, Y, Z, m and n havethe same significance as above.

In the process, the desired product of this invention is prepared by thesynthesis of an ordinary acid amide. As a particularly preferredprocess, there is an acid chloride process, another process wherein acondensing agent such as dicyclohexylcarbodiimide is used, and analternative process wherein an active ester such as chlorocarbonic acidester is used. The synthesis of the acid amide is usually performed inan inert solvent such as, preferably, chloroform, ether,tetrahydrofuran, benzene, etc. Also, there is no particular restrictionabout the reaction temperature but it is preferred to perform thereaction at room temperature or under heating.

Other Production Processes

The desired product of formula I₂ in Production process 2 wherein n is 2and Y is hydrogen atom, a lower alkyl group, an aryl group, or anaralkyl group can be also obtained by reacting the alcohol or thiolrepresented by the general formula

    Het--(CH.sub.2).sub.m --Z--H                               II.sub.3

wherein Het, Z and n have the same significance as above and acrylicamide or a derivative thereof under heating in the presence of a basesuch as sodium alkoxide.

Furthermore, as an alternative process of producing the desired productsof this invention, there is a process of converting mutually R₁ of thedesired product of formula I wherein X is ═N--R₁. For example, there arethe following processes:

(i) The desired product of formula I wherein R₁ is a cyano group isobtained by reacting the hydrochloride of the corresponding compound offormula I wherein R₁ is hydrogen atom and the monosodium salt ofcyanamide.

(ii) The desired product of formula I wherein R₁ is a carbamoyl group ora thiocarbamoyl group can be prepared as follows:

(a) The compound of formula I wherein R₁ is a carbamoyl group isobtained by passing dry hydrogen chloride gas through an alcoholcontaining the compound of formula I wherein R₁ is a cyano group, whilecooling or treating said compound with concentrated hydrochloric acidand by further treating the product with phosphorus pentasulfide; theproduct is converted into a compound of formula I wherein R₁ is athiocarbamoyl group.

(b) The compound of formula I wherein R₁ is a carbamoyl group or athiocarbamoyl group is obtained by reacting the compound of formula Iwherein R₁ is hydrogen atom and an isocyanic acid derivative such asmethyl isocyanate or an isothiocyanic acid derivative such asmethylisocyanate.

(iii) The desired product of formula I wherein X and Y combine with eachother to form a pyrimidine-2-yl group or a dihydropyrimidine-2-yl groupis obtained by reacting a compound of formula I whether R₁ is hydrogenatom and Y is a hydrogen atom or a lower alkyl group and cyanoaceticacid ethyl ester, malonic acid diethyl ester, acetoacetic acid ethylester, etc.

(iv) The compound of formula I wherein X is an imino group (═NH) and Yis a halogen-substituted alkanoyl group is obtained by reacting thecompound shown by the formula ##STR5## wherein Het, Z, m and n have thesame significance as above and a halogenoacetic acid ester.

Then, the process of this invention will further be explained by thefollowing examples. In addition, the starting compounds used in theprocess of this invention can be prepared according to the processesshown in the following reaction formulae, the details of which will bedescribed in the examples. ##STR6##

EXAMPLE 1 ##STR7##

(a) To 28.5 g. of 2-hydroxymethyl pyridine was added 0.3 g. of sodiummethoxide and while maintaining the reaction mixture at 40°-50° C. withice-cold water, 14 g. of acrylonitrile was added dropwise to the mixturegradually with stirring. Thereafter, the reaction mixture was stirredfor one hour at 50° C. and after adding thereto 0.33 g. of acetic acid,the mixture was distilled under reduced pressure to provide 38.9 g. ofoily 3-(2-pyridylmethoxy)propionitrile. Boiling point: 102°-104° C. (0.2mm. Hg).

(b) In 14.2 g. of absolute ethanol was dissolved 10 g.3-(2-pyridylmethoxy)propionitrile and while cooling the solution to0°-5° C., 5 g. of a dry hydrogen chloride gas was added into thesolution. The solution was allowed to stand for one week in arefrigerator. Then, 30 ml. of dry ether was added to the solution and15.0 g. of the crystals of ethyl 3-(2-pyridylmethoxy)propionimidatedihydrochloride were recovered by filtration. The crystals weredissolved in 30 ml. of ice water, after being alkalified with potassiumcarbonate, the solution was extracted three times each time with 40 ml.of ether, and the ether layers were dried over potassium carbonate.Then, the solvent was distilled off under reduced pressure to provide10.8 g. of ethyl 3-(2-pyridylmethoxy)propionimidate.

(c) In 3 ml. of dry ethanol was dissolved 5.0 g. of ethyl3-(2-pyridylmethoxy)propionimidate and then 1.1 g. of cyanamide wasadded to the solution. After allowing to stand the mixture for 30minutes at room temperature, the solvent was distilled off under reducedpressure and the residue was purified by means of silica gel columnchromatography using methylene chloride-ethyl acetate as an eluent andrecrystallized from ethyl acetate-ether to provide 1.2 g. ofN-cyano-3-(2-pyridylmethoxy)propionamidine showing a melting point of87°-89° C.

    ______________________________________                                        Elemental analysis for C.sub.10 H.sub.12 N.sub.4 O:                                    C          H       N                                                 ______________________________________                                        Calculated:                                                                              58.81%       5.92%   27.43%                                        Found:     58.13%       5.93%   27.83%                                        ______________________________________                                    

EXAMPLE 2 ##STR8##

In 30 ml. of dry ethanol was dissolved 7 g. of ethyl3-(2-pyridylmethoxy)propionimidate dihydrochloride and after cooling thesolution to 0°-5° C. with ice-cold water, 2.5 g. of triethylamine andthen 1.0 g. of cyanamide were added to the solution followed by stirringfor 3 hours at room temperature. Then, the solvent was distilled offunder reduced pressure and the residue formed was mixed with 30 ml. ofwater and extracted three times each time with 40 ml. of methylenechloride. The methylene chloride layer was washed with water, dried overanhydrous magnesium sulfate, and concentrated under reduced pressure toprovide 4.0 g. of ethyl N-cyano-3-(2-pyridylmethoxy)propionimidate. Theproduct was dissolved in 10 ml. of dry methanol and after adding thereto10 ml. of a 40% methanol solution of methylamine, the mixture wasallowed to stand for 30 minutes at room temperature. Then, the reactionmixture was concentrated under reduced pressure and the residue waspurified by silica gel column chromatography using a mixed solvent ofmethylene chloride and ethyl acetate as an eluant to provide 2.0 g. ofoily N-cyano-N'-methyl-3-(2-pyridylmethoxy)-propionamidine.

Infrared absorption spectrum (neet): 2170 cm.⁻¹

Nuclear magnetic resonance spctra (CDCl₃). δ: 2.93 (3H, d, J═5 Hz,--NHCH₃); 2.99 (2H, t, J═6 Hz, OCH₂ CH₂); 3.85 (2H, t, J═6 Hz, OCH₂CH₂); 4.70 (2H, s, --CH₂ O--CH₂ O--CH₂ CH₂); 7.2˜9.2 (5H, ##STR9##NHCH₃)

Mass spectrum: m/e 218(M⁺), 188, 163

EXAMPLE 3 ##STR10##

In 30 ml. of dry ethanol was dissolved 5.6 g. of ethylN-cyano-3-(2-pyridylmethoxy)propionimidate and the solution was addeddropwise to a solution of 0.77 g. of hydrazine in 20 ml. of dry ethanolfollowed by stirring for one hour at room temperature. The solvent wasdistilled off under reduced pressure and the residue formed wasrecrystallized from a mixed solvent of ethanol and ether to provide 1.85g. of the crystals of3-amino-5[2-(2-pyridyl)methoxy]ethyl-1,2,4-triazole showing a meltingpoint of 124°-125° C.

    ______________________________________                                        Elemental analysis for C.sub.10 H.sub.13 N.sub.5 O:                                    C          H       N                                                 ______________________________________                                        Calculated:                                                                              54.78%       5.98%   31.94%                                        Found:     54.60%       6.05%   31.91%                                        ______________________________________                                    

EXAMPLE 4 ##STR11##

In 30 ml. of dry ethanol was dissolved 2 g. of hydroxylaminehydrochloride and after cooling the solution to 0°-5° C. with ice-coldwater, 2.9 g. of triethylamine and then 30 ml. of a dry ethanol solutionof 7.0 g. of ethyl N-cyano-3-(2-pyridylmethoxy)propionimidate were addeddropwise to the solution. Then, the mixture was allowed to rise to roomtemperature followed by stirring for one hour. The solvent was distilledoff under reduced pressure and the residue formed was purified by meansof a silica gel column chromatography using a mixed solvent of methylenechloride and ethyl acetate as an eluant and recrystallized from a mixedsolvent of ethyl acetate and n-hexane to provide 1.3 g. of the colorlesscrystals of 5-amino-3-[2-(2-pyridylmethoxy)ethyl]-1,2,4-oxadiazoleshowing a melting point of 120°-122° C.

    ______________________________________                                        Elemental analysis for C.sub.10 H.sub.12 N.sub.4 O.sub.2 :                             C          H       N                                                 ______________________________________                                        Calculated:                                                                              54.54%       5.49%   25.44%                                        Found:     54.37%       5.37%   25.22%                                        ______________________________________                                    

EXAMPLE 5 ##STR12##

(a) To 13 g. of 2-mercaptomethyl pyridine was added 0.15 g. of sodiummethoxide and while maintaining the reaction mixture at 40°-50° C. withice-cold water, 5.2 g. of acrylnitrile was added dropwise gradually tothe mixture with stirring. Thereafter, the reaction mixture was stirredfor one hour at 50° C., 0.15 g. of acetic acid was added to the mixture,and the reaction mixture was distilled under reduced pressure to provide15.1 g. of oily 3-(2-pyridylmethylthio)propionitrile showing a boilingpoint of 124°-125° C. (0.4 mm.Hg).

(b) In 53.1 g. of dry ethanol was dissolved 41.1 g. of3-(2-pyridylmethylthio)propionitrile and while cooling the solution to0°-5° C. with ice-cold water, 18.5 g. of dry hydrogen chloride gas wasadded to the solution. The reaction mixture was allowed to stand for oneweek in a refrigerator and the crystals deposited were recovered byfiltration to provide 60 g. of ethyl3-(2-pyridylmethylthio)propionimidate dihydrochloride. The product couldbe converted into the free imidate as in the case of Example 1-(b).

(c) In 10 ml. of dry ethanol was dissolved 10 g. of ethyl3-(2-pyridylmethylthio)propionimidate and after adding thereto 1.7 g. ofcyanamide, the mixture was allowed to stand for 30 minutes at roomtemperature. Then, the solvent was distilled off under reduced pressureand the residue was purified by means of a silica gel columnchromatography using a mixed solvent of methylene chloride and ethylacetate as an eluant and recrystallized from a mixed solvent of ethylacetate and ether to provide 4.5 g. of N-cyano-3-(2-pyridyl)-methylthiopropionamidine showing a melting point of 110°-112° C.

    ______________________________________                                        Elemental analysis for C.sub.10 H.sub.12 N.sub.4 S:                                    C          H       N                                                 ______________________________________                                        Calculated:                                                                              54.52%       5.49%   25.43%                                        Found:     54.48%       5.38%   25.06%                                        ______________________________________                                    

EXAMPLE 6 ##STR13##

In 15 ml. of dry ethanol was dissolved 1.0 g. ofN-cyano-3-(2-pyridylmethoxy)propionamidine and after cooling thesolution to 0°-5° C. with ice-water, a dry hydrogen chloride gas waspassed through the solution for one hour. Then, the solvent wasdistilled off under reduced pressure and the residue was recrystallizedfrom a mixed solvent of ethanol and ether to provide 1.55 g. ofN-carbamoyl-3-(2-pyridylmethoxy)propionamidine dihydrochloride showing amelting point of 85°-89° C.

    ______________________________________                                        Elemental analysis for C.sub.10 H.sub.16 N.sub.4 O.sub.2 Cl.sub.2.1/2H.sub    .2 O:                                                                                  C          H       N                                                 ______________________________________                                        Calculated:                                                                              39.49%       5.63%   18.42%                                        Found:     39.87%       5.94%   18.15%                                        ______________________________________                                    

EXAMPLE 7 ##STR14##

By following the same procedure as in Example 6 using 1.0 g. ofN-cyano-3-[(2-pyridyl)methylthio]propionamide, 1.36 g. ofN-carbamoyl-3-(2-pyridylmethylthio)propionamide dihydrochloride wasobtained.

Melting point: 136°-141° C. (decompd.)

    ______________________________________                                        Elemental analysis for C.sub.10 H.sub.16 N.sub.4 OSCl.sub.2 :                          C          H       N                                                 ______________________________________                                        Calculated:                                                                              38.59%       5.18%   18.00%                                        Found:     38.48%       5.32%   17.25%                                        ______________________________________                                    

EXAMPLE 8 ##STR15##

(a) In 150 ml. of dry ethanol was dissolved 2.76 g. of metallic sodiumin nitrogen gas stream and then a solution of 15 g. of 2-pyridinethiomethanol in 30 ml. of dry ethanol was added to the solution at roomtemperature followed by stirring for 2 hours. Then, the mixture wascooled to 0°-5° C. and a solution of 9.06 g. of chloroacetonitrile in 20ml. of dry ethanol was added dropwise to the mixture followed bystirring for 18 hours at room temperature. Thereafter, the solvent wasdistilled off under reduced pressure and the residue was dissolved in 50ml. of water and extracted three times each time with 50 ml. ofdichloromethane. The dichloromethane layer was washed with water, driedover anhydrous magnesium sulfate, and concentrated under reducedpressure to provide 21.3 g. of oily 2-pyridylmethylthioacetonitrile.

(b) In 21.5 g. of dry ethanol was dissolved 15.3 g. of2-pyridylmethylthioacetonitrile and after adding 7.5 g. of a dryhydrogen chloride gas into the solution under cooling to 0°-5° C., thereaction mixture was allowed to stand for one week in a refrigerator.Then, 20 ml. of dry ether was added to the reaction mixture to depositecompletely crystals, which were recovered by filtration to provide 24.4g. of 2-pyridylmethylthioacetimidate dihydrochloride. An aqueoussolution of the product was alkalified with potassium carbonate and thenextracted with ether to provide the free imidate.

(c) In 30 ml. of dry ethanol was dissolved 10 g. of ethyl2-pyridylmethylthioacetimidate dihydrochloride and after cooling thesolution to 0°-5° C., a solution of 3.5 g. of triethylamine in 10 ml. ofdry ethanol was added dropwise to the solution. The mixture was allowedto raise to room temperature and 1.5 g. of cyanamide was added theretofollowed by stirring for 3 hours. Then, the solvent was distilled offunder reduced pressure and the residue was dissolved in 50 ml. of waterand extracted three times each time with 60 ml. of ether. The etherlayer was washed with water, dried over anhydrous magnesium sulfate, andconcentrated under reduced pressure to provide 7.6 g. of crude ethylN-cyano-2-pyridylmethylthioacetimidate.

(d) The product obtained in step (c) was dissolved in 10 ml. of methanoland after adding 10 ml. of a methanol solution of 40% methylamine, themixture was allowed to stand for 15 minutes at room temperature. Then,the reaction mixture was concentrated under reduced pressure and theresidue was purified by means of a silica gel column chromatographyusing a mixed solvent of methylene chloride and ethyl acetate as aneluant and recrystallized from a mixed solvent of ethyl acetate andether to provide 3.9 g. of the colorless crystals ofN-cyano-N'-methyl-2-(2-pyridylmethylthio)acetamidine showing a meltingpoint of 73°-74° C.

    ______________________________________                                        Elemental analysis for C.sub.10 H.sub.12 N.sub.4 S:                                    C          H       N                                                 ______________________________________                                        Calculated:                                                                              54.52%       5.49%   25.43%                                        Found:     54.54%       5.45%   25.76%                                        ______________________________________                                    

EXAMPLE 9 ##STR16##

In 20 ml. of dry ethanol was dissolved 2.35 g. of ethylN-cyano-2-pyridylmethylthioacetimidate obtained as in Example 8 (a), (b)and (c) described above and after adding 5 ml. of dry ethanol solutionof 0.59 g. of n-propylamine, the mixture was allowed to stand for 30minutes at room temperature. Then, the reaction mixture was concentratedunder reduced pressure and the residue was purified by means of a silicagel column chromatography using a mixed solvent of methylene chlorideand ethyl acetate as an eluant and recrystallized from a mixed solventof ethyl acetate and n-hexane to provide 1.1 g. of the colorless platesof N-cyano-N'-propyl-2-(2-pyridylmethylthio)acetamidine showing amelting point of 54°-56° C.

    ______________________________________                                        Elemental analysis for C.sub.12 H.sub.16 N.sub.4 S:                                    C          H       N                                                 ______________________________________                                        Calculated:                                                                              58.04%       6.49%   22.56%                                        Found:     57.95%       6.53%   22.77%                                        ______________________________________                                    

EXAMPLE 10 ##STR17##

By following the same procedure as in Example 9 using 2.35 g. of ethylN-cyano-2-pyridylmethylthioacetimidate and 0.61 g. of ethanolamine, 0.75g. of N-cyano-N'-(2-hydroxyethyl)-2-(2-pyridylmethylthio)acetamidineshowing a melting point of 68°-69° C. was obtained.

    ______________________________________                                        Elemental analysis for C.sub.11 H.sub.14 N.sub.4 OS:                                   C          H       N                                                 ______________________________________                                        Calculated:                                                                              52.78%       5.64%   22.38%                                        Found:     52.82%       5.58%   22.57%                                        ______________________________________                                    

EXAMPLE 11 ##STR18##

In 40 ml. of dry ethanol was dissolved 21.0 g. of ethyl4-(2-pyridylmethylthio)butylimidate prepared by following the sameprocedure as in Example 8 (a) using 4-chlorobutyronitrile in place ofchloroacetonitrile and treating the product as in Example 8 (b) andafter adding to the solution 4 g. of cyanamide, the mixture was allowedto stand for 30 minutes at room temperature. Then, the reaction mixturewas concentrated under reduced pressure and the residue was purified bymeans of a silica gel column chromatography using a mixed solvent ofmethylene chloride and ethyl acetate and recrystallized from a mixedsolvent of ethanol and ether to provide 9.6 g. ofN-cyano-4-(2-pyridylmethylthio)butyramidine showing a melting point of96°-97° C.

    ______________________________________                                        Elemental analysis for C.sub.11 H.sub.14 N.sub.4 S:                                   C           H       N                                                 ______________________________________                                        Calculated:                                                                             56.38%        6.02%   23.91%                                        Found:    55.67%        6.01%   23.73%                                        ______________________________________                                    

EXAMPLE 12 ##STR19##

By following the same procedure as in Example 6 usingN-cyano-4-(2-pyridylmethylthio)butyramidine,N-carbamoyl-4-(2-pyridylmethylthio)butyramidine dihydrochloride wasobtained.

Melting point: 160°-165° C. (decompd.)

    ______________________________________                                        Elemental analysis for C.sub.11 H.sub.18 N.sub.4 SCl.sub.2.H.sub.2 O:                      N                                                                ______________________________________                                               Calculated:                                                                           17.12%                                                                Found:  16.97%                                                         ______________________________________                                    

EXAMPLE 13 ##STR20##

In 80 ml. of dry ethanol was dissolved 15 g. of ethyl3-(2-pyridylmethylthio)propionimidate dihydrochloride and after coolingthe solution to 0°-5° C., 5.1 g. of triethylamine was added to thesolution. The mixture was allowed to raise to room temperature and 2.1g. of cyanamide was added to the mixture followed by stirring for 1.5hours. The reaction mixture was then concentrated under reduced pressureand the residue was mixed with 50 ml. of water and extracted three timeseach time with 60 ml. of ether. The ether layer was washed with waterand dried over anhydrous magnesium sulfate. Then, the solvent wasdistilled off under reduced pressure and the residue formed wasdissolved in 20 ml. of dry methanol and mixed with 20 ml. of a 40%methanol solution of methylamine. The mixture was allowed to stand for15 minutes at room temperature and then concentrated under reducedpressure. The residue formed was purified by means of a silica gelcolumn chromatography using a mixed solvent of methylene chloride andethyl acetate and recrystallized from a mixture of ethyl acetate andether to provide 2.5 g. ofN-cyano-N'-methyl-3-(2-pyridylmethylthio)propionamidine showing amelting point of 49°-51° C.

    ______________________________________                                        Elemental analysis for C.sub.11 H.sub.14 N.sub.4 S:                           ______________________________________                                        Calculated:  N             23.91%                                             Found:       N             23.79%.                                            ______________________________________                                    

EXAMPLE 14 ##STR21##

By following the same procedure as in Example 6 usingN-cyano-N'-methyl-3-(2-pyridylmethylthio)propionamidine,N-carbamoyl-N'-methyl-3-(2-pyridylmethylthio)propionamidine,dihydrochloride showing a melting point of 155°-160° C. (decompd.) wasobtained.

    ______________________________________                                        Elemental analysis for C.sub.11 H.sub.18 N.sub.4 SCl.sub.2.2H.sub.2           ______________________________________                                        Calculated:  N             16.23%                                             Found:       N             16.37%.                                            ______________________________________                                    

EXAMPLE 15 ##STR22##

In 50 ml, of dry ethanol was dissolved 7.0 g. of ethyl3-(2-pyridylmethylthio)propionimidate and a solution of 3.5 g. ofacetohydrazide in 20 ml. of dry ethanol was added to the solution withstirring, the reaction was performed for one hour at room temperature.

The solvent was distilled off under reduced pressure and the residue wasrecrystallized from a mixture of ethanol and ether to provide thecolorless crystals of N-acetyl-3-(2-pyridylmethylthio)propionamidrazoneshowing a melting point of 149°-150.5° C.

    ______________________________________                                        Elemental analysis for C.sub.11 H.sub.16 N.sub.4 OS:                                   C          H       N                                                 ______________________________________                                        Calculated:                                                                              52.36%       6.39%   22.20%                                        Found:     52.38%       6.43%   22.38%                                        ______________________________________                                    

EXAMPLE 16 ##STR23##

1.7 g. of N-acetyl-3-(2-pyridylmethylthio)-propionamidrazone was heatedin an oil bath at 155° C. for 10 minutes, the reaction mixture wasallowed to cool to room temperature and dissolved in 20 ml. of dryethanol. The product was treated with an ethanol solution of hydrogenchloride. Then, the solvent was distilled off under reduced pressure andthe residue was recrystallized from a mixture of ethanol and ether toprovide 1.7 g. of the colorless crystals of3-methyl-5-[2-(2-pyridylmethylthio)ethyl]-1,2,4-triazole dihydrochlorideshowing a melting point of 239°-241° C.

    ______________________________________                                        Elemental analysis for C.sub.11 H.sub.16 N.sub.4 SCl.sub.2.H.sub.2 O:                  C          H       N                                                 ______________________________________                                        Calculated:                                                                              40.62%       5.58%   17.23%                                        Found:     41.04%       5.18%   17.52%                                        ______________________________________                                    

EXAMPLE 17 ##STR24##

In 20 ml. of dry ethanol was dissolved 5.7 g. of ethylN-cyano-2-pyridylmethylthioacetimidate and after cooling the solution to0°-5° C., acetamidine (prepared by liberating 2.3 g. of acetamidinehydrochloride with a solution of 0.57 g. of sodium in 20 ml. of ethanoland filtering off sodium chloride thus formed) was added to thesolution. The mixture was allowed to raise to room temperature followedby stirring for one hour and concentrated under reduced pressure. Theresidue was mixed with 30 ml. of water and extracted three times eachtime with 40 ml. of methylene chloride. The methylene chloride layer waswashed with water, dried over anhydrous magnesium sulfate, andconcentrated under reduced pressure. The residue was recrystallized fromethyl acetate to provide 1.6 g. of the colorless crystals of2-amino-4-methyl-6-(2-pyridylmethylthio)methyl-1,3,5-triazine showing amelting point of 99.5°-101° C.

    ______________________________________                                        Elemental analysis for C.sub.11 H.sub.13 N.sub.5 S:                                    C          H       N                                                 ______________________________________                                        Calculated:                                                                              53.42%       5.30%   28.32%                                        Found:     53.26%       5.10%   28.39%                                        ______________________________________                                    

EXAMPLE 18 ##STR25##

In 20 ml. of a 40% methanol solution of methylamine was dissolved 5.0 g.of ethyl 3-(2-pyridylmethylthio)propionimidate and after allowing thesolution to stand for 20 hours at room temperature, the reaction mixturewas concentrated under reduced pressure. Then, the residue formed waspurified by means of a silica gel column chromatography using a mixedsolvent of methylene chloride and ethyl acetate as an eluant and afteradding an equimolar amount of hydrochloric acid, the product wasrecrystallized from a mixture of ethanol and ether to provide 2.0 g. ofN,N'-dimethyl-3-(2-pyridylmethylthio)propionamidine hydrochlorideshowing a melting point of 142°-143° C.

    ______________________________________                                        Elemental analysis for C.sub.11 H.sub.18 N.sub.3 SCl:                                   C     H         N       Cl                                          ______________________________________                                        Calculated: 50.85%  6.98%     16.18%                                                                              13.65%                                    Found:      51.03%  6.92%     16.12%                                                                              13.40%                                    ______________________________________                                    

EXAMPLE 19 ##STR26##

Ethyl 3-(2-pyridylmethylthio)propionimidate was reacted with anequimolar amount of ammonium chloride in methanol for 2 hours at roomtemperature and the product was recrystallized from a mixture of ethanoland ether to provide 3-(2-pyridylmethylthio)propionamidinedihydrochloride showing a melting point of 140°-143° C.

    ______________________________________                                        Elemental analysis for C.sub.9 H.sub.15 N.sub.3 SCl.sub.2 :                            C          H       N                                                 ______________________________________                                        Calculated:                                                                              40.30%       5.64%   15.67%                                        Found:     39.97%       5.67%   15.68%                                        ______________________________________                                    

EXAMPLES 20-33 ##STR27##

To an absolute ethanol solution of ethyl3-(2-pyridylmethylthio)propionimidate was added 1.5-5 equivalent ofamine (RNH₂) and the mixture was allowed to stand for 24 hours at roomtemperature. Then, the solvent was distilled off under reduced pressure.The crystallized residue was recrystallized from a proper solvent, whilethe other residue was purified by means of a silica gel columnchromatography using a mixed solvent of methylene chloride and methanoland treated with hydrochloric acid to provide a hydrochloride, which wasrecrystallized. By the procedures described above, the followingproducts were obtained.

EXAMPLE 20

    ______________________________________                                        Desired Compound                                                               ##STR28##                                                                    4(5)-Ethoxycarbonyl-5(4)-hydroxy-2-[2-(2-pyridyl-                             methylthio)ethyl]imidazole                                                    Reagent amine                                                                  ##STR29##                                                                    Recrystallization solvent                                                     Ethanol-Ether                                                                 melting point                                                                 185-187° C.                                                            ______________________________________                                        Elemental analysis for C.sub.14 H.sub.17 N.sub.3 O.sub.3 S                               C            H       N                                             ______________________________________                                        Calculated:                                                                              57.41%       5.57%   13.67%                                        Found:     57.80%       5.60%   13.70%                                        ______________________________________                                    

EXAMPLE 21

    ______________________________________                                        Desired Compound                                                               ##STR30##                                                                    3-(2-Pyridylmethylthio)propionamide oxime (Oily)                              ______________________________________                                    

Reagent amine: NH₂ OH.

Nuclear magnetic resonance spectra (CDCl₃). δ: 2.38 (2H, t), 2.70(2H,t), 3.86 (2H,s), 7.0-8.6 (4H).

Mass spectrum: (Trimethylsilylated) m/e 355, 340

EXAMPLE 22

    ______________________________________                                        Desired Compound                                                               ##STR31##                                                                    NBenzoyl-3-(2-pyridylmethylthio)propionamidrazone                             Reagent amine                                                                  ##STR32##                                                                    Recrystallization solvent                                                     Ethanol-Ether                                                                 melting point                                                                 138-139° C.                                                            ______________________________________                                        Elemental analysis for C.sub.16 H.sub.18 N.sub.4 OS                                      C            H       N                                             ______________________________________                                        Calculated:                                                                              61.12%       5.77%   17.82%                                        Found:     61.05%       5.76%   18.15%                                        ______________________________________                                    

EXAMPLE 23

    ______________________________________                                        Desired Compound                                                               ##STR33##                                                                    NEthoxycarbonyl-3-(2-pyridylmethylthio)propionamidrazone                      Reagent amine                                                                 NH.sub.2 NHCOOCH.sub.2 CH.sub.3                                               Recrystallization solvent                                                     Methanol-Ether                                                                melting point                                                                 129.5-131° C.                                                          ______________________________________                                        Elemental analysis for C.sub.12 H.sub.18 N.sub.4 O.sub.2 S                               C            H       N                                             ______________________________________                                        Calculated:                                                                              51.05%       6.43%   19.84%                                        Found:     50.84%       6.34%   19.82%                                        ______________________________________                                    

EXAMPLE 24

    ______________________________________                                        Desired Compound                                                               ##STR34##                                                                    N[(2-Pyridyl)carbonyl]-3-(2-pyridylmethylthio)-                               propionamidrazone                                                             Reagent amine                                                                  ##STR35##                                                                    Recrystallization solvent                                                     Ethanol-n-Hexane                                                              melting point                                                                 127-129° C.                                                            ______________________________________                                        Elemental analysis for C.sub.15 H.sub.17 N.sub.5 OS                                      C            H       N                                             ______________________________________                                        Calculated:                                                                              57.12%       5.43%   22.21%                                        Found:     57.08%       5.44%   22.56%                                        ______________________________________                                    

EXAMPLE 25

    ______________________________________                                        Desired Compound                                                               ##STR36##                                                                    NBenzenesulfonyl-3-(2-pyridylmethylthio)-                                     propionamidrazone                                                             Reagent amine                                                                  ##STR37##                                                                    Recrystallization                                                             Aceton-n-Hexane                                                               melting point                                                                 119-121° C.                                                            ______________________________________                                        Elemental analysis for C.sub.15 H.sub.18 N.sub.4 O.sub.2 S.sub.2                         C            H       N                                             ______________________________________                                        Calculated:                                                                              51.41%       5.18%   15.99%                                        Found:     51.20%       5.12%   15.93%                                        ______________________________________                                    

EXAMPLE 26

    ______________________________________                                        Desired Compound                                                               ##STR38##                                                                    N(2-Propynyl)-3-(2-pyridylmethylthio)propion-                                 amidine dihydrochloride                                                       Reagent amine                                                                 NH.sub.2 CH.sub.2 CCH                                                         Recrystallization solvent                                                     Ethanol-Ether                                                                 melting point                                                                 159-161° C.                                                            ______________________________________                                        Elemental analysis for C.sub.12 H.sub.17 N.sub.3 SCl.sub.2                               C            H       N                                             ______________________________________                                        Calculated:                                                                              47.06%       5.59%   13.72%                                        Found:     46.78%       5.63%   13.68%                                        ______________________________________                                    

EXAMPLE 27

    ______________________________________                                        Desired Compound                                                               ##STR39##                                                                    N(4-Chlorobenzyl)-3-(2-pyridylmethylthio)-                                    propionamidine dihydrochloride                                                Reagent amine                                                                  ##STR40##                                                                    Recrystallization solvent                                                     aq. Ethanol                                                                   melting point                                                                 193-195° C. (dec.)                                                     ______________________________________                                        Elemental analysis for C.sub.16 H.sub.20 N.sub.3 SCl.sub.3                               C            H       N                                             ______________________________________                                        Calculated:                                                                              48.93%       5.13%   10.70%                                        Found:     48.72%       5.11%   10.50%                                        ______________________________________                                    

EXAMPLE 28

    ______________________________________                                         Desired Compound                                                              ##STR41##                                                                    NOxamoyl-3-(2-pyridylmethylthio)-propionamidrazone                            Reagent amine                                                                  ##STR42##                                                                    ______________________________________                                    

Recrystallization solvent: Ethanol.

melting point: 149°-150° C.

Nuclear magnetic resonance spectra (DMSO-d₆). δ: 2.93 (4H, m), 3.86 (2H,s), 7.0˜8.6 (4H).

Mass spectrum: m/e 281(M⁺), 263.

EXAMPLE 29

    ______________________________________                                        Desired Compound                                                               ##STR43##                                                                    NAllyl-3-(2-pyridylmethylthio)propionamidine                                  dihydrochloride                                                               Reagent amine                                                                 NH.sub.2 CH.sub.2 CHCH.sub.2                                                  Recrystallization solvent                                                     Isopropanol                                                                   melting point                                                                 152-155° C. (dec.)                                                     ______________________________________                                        Elemental analysis for C.sub.12 H.sub.19 N.sub.3 SCl.sub.2                               C            H       N                                             ______________________________________                                        Calculated:                                                                              46.76%       6.21%   13.63%                                        Found:     46.25%       6.29%   13.68%                                        ______________________________________                                    

EXAMPLE 30

    ______________________________________                                        Desired Compound                                                               ##STR44##                                                                    3-(2-Pyridylmethylthio-N2,2,2-trifluoro-                                      ethylpropionamidine dihydrochloride                                           Reagent amine                                                                 CF.sub.3 CH.sub.2 NH.sub.2                                                    Recrystallization solvent                                                     Ethanol-Ether                                                                 melting point                                                                 188-191° C.                                                            ______________________________________                                        Elemental analysis for C.sub.11 H.sub.16 N.sub.3 SF.sub.3 Cl.sub.2                       C            H       N                                             ______________________________________                                        Calculated:                                                                              37.72%       4.60%   12.00%                                        Found:     37.76%       4.74%   11.96%                                        ______________________________________                                    

EXAMPLE 31

    ______________________________________                                        Desired Compound                                                               ##STR45##                                                                    NCyclopropyl-3-(2-pyridylmethylthio)propion-                                  amidine dihydrochloride                                                       Reagent amine                                                                  ##STR46##                                                                    Recrystallization solvent                                                     Ethanol-Ether                                                                 melting point                                                                 155-158° C.                                                            ______________________________________                                        Elemental analysis for C.sub.12 H.sub.19 N.sub.3 SCl.sub.2                               C            H       N                                             ______________________________________                                        Calculated:                                                                              46.76%       6.21%   13.63%                                        Found:     46.50%       6.44%   13.38%                                        ______________________________________                                    

EXAMPLE 32

    ______________________________________                                        Desired Compound                                                               ##STR47##                                                                    NPhenyl-3-(2-pyridylmethylthio)propionamidrazone                              dihydrochloride                                                               Reagent amine                                                                  ##STR48##                                                                    Recrystallization solvent                                                     Ethanol-Ether                                                                 melting point                                                                 153-155° C. (dec.)                                                     ______________________________________                                        Elemental analysis for C.sub.15 H.sub.20 N.sub.4 SCl.sub.2.3/2H.sub.2 O                  C            H       N                                             ______________________________________                                        Calculated:                                                                              46.82%       5.63%   14.56%                                        Found:     46.59%       5.67%   14.42%                                        ______________________________________                                    

EXAMPLE 33

    ______________________________________                                        Desired Compound                                                               ##STR49##                                                                    NTrifluoroacetyl-3-(2-pyridylmethylthio)-                                     propionamidine                                                                Reagent amine                                                                 NH.sub.2 COCF.sub.3                                                           Recrystallization solvent                                                     Ethylacetate-Ether                                                            melting point                                                                 113-116° C.                                                            ______________________________________                                        Elemental analysis for C.sub.11 H.sub.12 N.sub.3 OSF.sub.3.H.sub.2 O          Calculated:                                                                              42.71%       4.56%   13.59%                                        Found:     42.90%       4.69%   13.74%                                        ______________________________________                                    

EXAMPLE 34 ##STR50##

In 30 ml. of dry ether was dissolved 2.7 g. of ethylN-cyano-3-(2-pyridylmethylthio)propionimidate and after adding 1.0 g. ofproparglyamine to the solution followed by stirring for one hour at roomtemperature, the solvent was distilled off under reduced pressure. Then,the residue formed was purified by means of a silica gel columnchromatography using a mixed solvent of methylene chloride and methanolas an eluant and recrystallized from a mixed solvent of ethyl acetateand n-hexane to provide 2.0 g. of the crystals ofN-cyano-N'-(2-propynyl)-3-(2-pyridylmethylthio)propionamidine showing amelting point of 99°-100° C.

    ______________________________________                                        Elemental analysis for C.sub.13 H.sub.14 N.sub.4 S:                                    C          H       N                                                 ______________________________________                                        Calculated:                                                                              60.44%       5.46%   21.69%                                        Found:     60.36%       5.43%   21.53%                                        ______________________________________                                    

EXAMPLE 35 ##STR51##

In 90 ml. of absolute methanol was dissolved 9.0 g. of3-(2-pyridylmethylthio)-propionamidine dihydrochloride and after adding50 ml. of a methanol solution of 3.6 g. of sodium methoxide to thesolution under cooling below 10° C., the reaction mixture was allowed torise to room temperature followed by stirring for one hour.

To the reaction mixture was added 50 ml. of a methanol solution of 2.4g. of methyl isothiocyanate and after stirring the mixture for 5 hoursat room temperature, the solvent was distilled off under reducedpressure. Then, the residue was purified by means of a silica gel columnchromatography using a mixed solvent of chloroform and methanol as aneluant treated with hydrochloric acid, and then recrystallized from amixed solvent of ethanol and ether to provide 1.1 g. ofN-(N-methylthiocarbamoyl)-3-(2-pyridylmethylthio)propionamidinedihydrochloride.

Melting point: 147°-152° C. (decompd.)

Nuclear magnetic resonance spectra (d₆ -DMSO): δ: 2.98 (3H, d, J═4 Hz,--NHCH₃); 3.09 (4H, s, --S--CH₂ CH₂ --); 4.39 (2H, s, ##STR52##7.80˜9.00 (4H, ##STR53##

EXAMPLE 36 ##STR54##

By following the same procedure as in Example 35 using methyl isocyanatein place of methyl isothiocyanate, 0.7 g.N-(N-methylcarbamoyl)-3-(2-pyridylmethylthio)propionamidinedihydrochloride was obtained from 11 g. of3-(2-pyridylmethylthio)propionamidine dihydrochloride.

Melting point: 141°-146° C. (decompd.)

Nuclear magnetic resonance spectra (d₆ -DMSO) δ: 2.70 (3H, d, J═4 Hz,--NHCH₃); 3.02 (4H, s, --S--CH₂ CH₂ --); 4.34 (2H, s, ##STR55##7.80˜9.00 (4H, ##STR56##

EXAMPLE 37 ##STR57##

After heating 0.5 g. ofN-picolinyl-3-(2-pyridylmethylthio)propionamidrazone to 130°-140° C. for15 minutes, the residue formed was purified by means of a silica gelcolumn chromatography using a mixed solvent of methylene chloride andmethanol as an eluant and recrystallized from a mixed solvent of ethylacetate and ether to provide 0.3 g. of3-(2-pyridyl)-5-[2-(2-pyridylmethylthio)ethyl]-1,2,4-triazole showing amelting point of 98°-100° C.

Nuclear magnetic resonance spectra (CDCl₃). δ: 3.08 (4H, m, --S--CH₂ CH₂--); 3.90 (2H, s, --CH₂ S--); 7.0˜8.80 (8H, ##STR58##

Mass spectrum: m/e 297(M⁺), 205.

EXAMPLE 38 ##STR59##

To 20 ml. of ice-cooled absolute ethanol solution of 2.0 g. of sodiummethoxide was added 20 ml. of an absolute ethanol suspension of 5.0 g.of 3-(2-pyridylmethylthio)propionamidine dihydrochloride and afterallowing to rise the mixture to room temperature followed by stirringfor 1.5 hours, 3.6 g. of methyl trichloroacetate was added to themixture. The resultant mixture was allowed to stand for 2 days at roomtemperature, the solvent was distilled off under reduced pressure, andthe residue was purified by means of a silica gel column chromatographyusing a mixed solvent of methylene chloride and methanol andrecrystallized from a mixture of ethanol and ether to provide 1.4 g. ofN-trichloroacetyl-3-(2-pyridylmethylthio)propionamidine showing amelting point of 119°-120° C.

    ______________________________________                                        Elemental analysis for C.sub.11 H.sub.12 N.sub.3 OSCl.sub.3.H.sub.2 O:                 C          H       N                                                 ______________________________________                                        Calculated:                                                                              36.84%       3.93%   11.72%                                        Found:     36.78%       3.94%   11.80%                                        ______________________________________                                    

EXAMPLES 39-40 ##STR60##

(a). In absolute ethanol was dissolved 12.2 g. of sodium in nitrogen gasstream and after cooling the solution to 0°-5° C., 50 ml. of an absoluteethanol solution of 23.1 g. of 3-mercaptopropionitrile was added to thesolution followed by stirring for one hour. To the mixture was added 800ml. of an absolute ethanol solution of 44.4 g. of4-methyl-5-chloromethylimidazole hydrochloride and after stirring for 2hours, the reaction mixture was allowed to rise to room temperaturefollowed by further stirring for 18 hours. Then, NaCl deposited wasfiltered off, the solvent was distilled off under reduced pressure, andthe residue was recrystallized from a mixture of ethanol and ether toprovide 46.8 g. of 3-(4-methyl-5-imidazolylmethylthio)propionitrile.

(b). In 150 ml. of absolute ethanol was dissolved 10.0 g. of3-(4-methyl-5-imidazolylmethylthio)propionitrile and after cooling thesolution to 0°-5° C., 4.8 g. of a dry hydrogen chloride gas was absorbedin the solution. The solution was allowed to stand for one week at 0°-5°C. Then, the solvent was distilled off under reduced pressure and thecrystals of ethyl 3-(4-methyl-5-imidazolylmethylthio)propionimidatedihydrochloride were washed with a mixed solvent of ethanol and etherand recovered by filtration. The amount of the product was 12.0 g.

(c). To an ice-cooled ethanol solution containing an equivalent ofsodium ethoxide was added ethyl3-(4-methyl-5-imidazolylmethylthio)propionimidate dihydrochloridefollowed by stirring for 15 minutes and after adding 1.5-5 equivalent ofan amine (RNH₂), the mixture was allowed to stand for 24 hours at roomtemperature. The solvent was distilled off under reduced pressure andthe residue was purified by means of a silica gel column chromatographyusing a mixed solvent of chloroform and methanol. If necessary, theproduct was treated with hydrochloric acid to form the hydrochloric ofthe product.

These are shown in the following table.

EXAMPLE 39

    ______________________________________                                        Desired Compound                                                               ##STR61##                                                                    NCyano-3-[(5-methylimidazol-4-yl)methylthio]-                                 propionamidine                                                                ______________________________________                                    

Reagent amine: NH₂ CN.

Recrystallization solvent: Isopropanol-Ethylacetate.

melting point: 147°-149° C.

Nuclear magnetic resonance spectra (DMSO-d₆). δ: 2.16 (3H,s), 2.70(4H,s), 3.70 (2H,s), 7.44 (1H,s).

EXAMPLE 40

    ______________________________________                                        Desired Compound                                                               ##STR62##                                                                    N2-Propynyl-3-[(5-methylimidazol-4-yl)methylthio]-                            propionamidine dihydrochloride (Caramel)                                      ______________________________________                                    

Reagent amine: NH₂ CH₂ C.tbd.CH.

Nuclear magnetic resonance spectra (DMSO-d₆). δ: 2.20 (3H,s), 2.85(4H,s), 3.44 (1H,t), 3.85 (2H,s), 4.21 (2H,d), 8.13 (1H,s).

EXAMPLES 41-42 ##STR63##

(a) To 95 g. of furfurylmercaptan was added 0.2 g. of sodium methoxideand 53 g. of acrylonitrile was added gradually to the mixture withstirring while maintaining the reaction temperature at 40°-50° C. Afterstirring the mixture for 30 minutes at 40°-50° C., the reaction mixturewas neutralized with 0.2 g. of acetic acid and distilled under reducedpressure to provide 135.5 g. of 3-(2-furanylmethylthio)-propionitrileshowing a boiling point of 92°-93° C. (0.1 mm.Hg).

(b) In 600 ml. of absolute ethanol were dissolved 40 g. of3-(2-furanylmethylthio)propionitrile, 39.0 g. of dimethylaminehydrochloride, and 16.7 g. of para-formaldehyde and the solution wasrefluxed for 24 hours. To the reaction mixture were added 39.0 g. ofdimethylamine hydrochloride and 16.7 g. of para-formaldehyde and themixture was further refluxed for 24 hours. Then, the solvent wasdistilled off under reduced pressure and the residue was mixed with 300ml. of water. The mixture was alkalified by the addition of potassiumcarbonate and extracted three times each time with 200 ml. of ethylacetate. The extract was dried over anhydrous potassium carbonate andthe solvent was distilled off under reduced pressure. Then, the residuewas distilled under reduced pressure to provide 41.6 g. of3-(5-dimethylaminomethyl-2-furanylmethylthio)propionitrile showing aboiling point of 131°-137° C. (0.25 mm. Hg).

(c) In a mixture of 4.5 g. of absolute ethanol and 60 ml. of anhydrouschloroform was dissolved 19.8 g. of5-dimethylaminoethyl-2-furanylmethylthio)propionitrile and after coolingthe solution to 0°-5° C., 6.5 g. of a dry hydrogen chloride gas wasadded into the solution. After allowing to stand the reaction mixture ina refrigerator for one week, the mixture was added to 150 ml. ofice-water containing excess potassium carbonate and the product wasextracted three times each time with 80 ml. of chloroform. The extractwas dried over anhydrous potassium carbonate and then the solvent wasdistilled off under reduced pressure to provide 23 g. of ethyl3-(5-dimethylaminomethyl-2-furanylmethylthio)propionimidate. The productwas used in the subsequent reaction as it was.

(d) In absolute ethanol was dissolved ethyl3-(5-dimethylaminomethyl-2-furanylmethylthio)propionimidate and afteradding thereto a stoichiometric amount or a slightly excessive amount ofan amine (RNH₂), the mixture was reacted for 24 hours at roomtemperature. Then, the solvent was distilled off under reduced pressureand, if necessary, the product was purified by means of a columnchromatography to provide the objective product as shown in thefollowing table.

EXAMPLE 41

    ______________________________________                                        Desired Compound                                                               ##STR64##                                                                    NCyano-3-[5-(dimethylaminomethyl)furfurylthio]-                               propionamidine                                                                Reagent amine                                                                 NH.sub.2 CN                                                                   Recrystallization solvent                                                     Ethylacetate-Ether                                                            melting point                                                                 70-72° C.                                                              Nuclear magnetic resonance spectra (CDCl.sub.3)                               δ:                                                                              2.22 (6H,s), 2.40 (2H,m), 2.84 (2H,t),                                        3.38 (2H,s), 3.72 (2H,s), 6.12 (2H,s)                                 Infrared absorption spectrum (KBr tab) cm.sup.-1 : 2180                       ______________________________________                                        Elemental analysis for C.sub.12 H.sub.18 N.sub.4 OS                                      C            H       N                                             ______________________________________                                        Calculated:                                                                              54.11%       6.81%   21.03%                                        Found:     54.15%       6.85%   21.22%                                        ______________________________________                                    

EXAMPLE 42

    ______________________________________                                        Desired Compound                                                               ##STR65##                                                                    3-[5-(Dimethylaminomethyl)furfurylthio]-N                                     2-propynylpropionamidine dihydrochloride                                      Reagent amine                                                                 NH.sub.2 CH.sub.2 CCH                                                         Recrystallization solvent                                                     Ethanol-Ether                                                                 melting point                                                                 176-178° C.                                                            Nuclear magnetic resonance spectra (DMSO-d.sub.6)                             δ:                                                                             2.68 (6H,s), 2.88 (4H,s), 3.44 (1H,t), 3.94 (2H,s)                            4.22 (2H,d), 4.36 (2H,s), 6.50 (1H,d), 3.70 (1H,d)                     ______________________________________                                        Elemental analysis for C.sub.14 H.sub.23 N.sub.3 OSCl.sub.2                              C            H       N                                             ______________________________________                                        Calculated:                                                                              47.73%       6.58%   11.93%                                        Found:     47.44%       6.91%   11.80%                                        ______________________________________                                    

EXAMPLE 43 ##STR66##

By following the same procedure as in Example 1-(a),3-(4-methyl-5-imidazolylmethoxy)propionitrile was obtained from4-hydroxylmethyl-5-methyl-imidazole and acrylonitrile and by treatingthe product as in Example 1-(b), ethyl3-(4-methyl-5-imidazolylmethoxy)propionimidate was obtained. Then, byfurther treating the product as in Example 1-(c),N-cyano-3-(4-methyl-5-imidazolylmethoxy)propionamidine was obtained.

Infrared absorption spectrum (cm.⁻¹): 2160.

Mass spectrum (m/c): 207 (M⁺).

EXAMPLE 44 ##STR67##

In 30 ml. of absolute ethanol was dissolved 1.0 g. ofN-cyano-3-(4-methyl-5-imidazolylmethylthio)propionamidine and aftercooling the solution to 0°-5° C., a dry hydrogen chloride gas was passedthrough the solution slowly for one hour. Then, the solvent wasconcentrated under reduced pressure and the crystals deposited wererecovered by filtration to provide 1.0 g. ofN-carbamoyl-3-(4-methyl-5-imidazolylmethylthio)-propionamidine showing amelting point of 169°-172.5° C.

    ______________________________________                                        Elemental analysis for C.sub.9 H.sub.17 N.sub.5 OSCl.sub.2.1/2H.sub.2 O:               C          H       N                                                 ______________________________________                                        Calculated:                                                                              33.49%       5.47%   21.70%                                        Found:     33.95%       5.43%   21.22%                                        ______________________________________                                    

Nuclear magnetic resonance spectra (d₆ -DMSO): δ: 2.32 (3H, s, --CH₃)3.00 (4H, s, --S--CH₂ --CH₂ --) 4.04 (2H, s, --CH₂ S--) 8.97 (1H, s,##STR68##

EXAMPLE 45 ##STR69##

To 2-hydroxymethylpyridine was added 50 mg. of sodium methoxide andwhile maintaining the temperature of the reaction mixture at 50°-60° C.with stirring, 3.3 g. of acrylamide was added to the solution. Thereaction mixture was stirred for 30 minutes at the same temperature, thecrystals deposited were recrystallized from a mixed solution of ethanoland ether to provide 8.5 g. of the crystals of3-(2-pyridylmethoxy)-propionamide showing a melting point of 94°-96° C.

    ______________________________________                                        Elemental analysis for C.sub.9 H.sub.12 N.sub.2 O.sub.2 :                             C           H       N                                                 ______________________________________                                        Calculated:                                                                             59.99%        6.71%   15.55%                                        Found:    59.80%        6.67%   15.45%                                        ______________________________________                                    

EXAMPLE 46 ##STR70##

(a) In 100 ml. of 47% hydrobromic acid were dissolved 4.86 g. of3-mercaptopropionic acid and 5 g. of 2-hydroxymethylpyridine and afterrefluxing the solution for 20 hours, the reaction mixture wasconcentrated under reduced pressure to provide 12.5 g. of sticky crude3-(2-pyridylmethylthio)-propionic acid hydrobromide.

(b) To 4 g. of crude 3-(2-pyridylmethylthio)propionic acid hydrobromidewas added 20 ml. dry chloroform and after cooling the mixture to 0°-5°C., 3.5 g. of triethylamine was added to the mixture followed bystirring for 30 minutes. Thereafter, a solution of 1.56 g. of ethylchlorocarbonate in 5 ml. of dry chloroform was added to the mixturefollowed by stirring for one hour.

Then, to the reaction mixture was added a solution of 1.3 g. ofn-propylamine in 5 ml. of dry chloroform and after allowing to rasie themixture to room temperature followed by stirring for 3 hours, 20 ml. ofchloroform was added to the mixture. The chloroform layer was washedwith water, dried over anhydrous magnesium sulfate, and concentratedunder reduced pressure. The residue was purified by means of a silicagel column chromatography using a mixed solvent of methylene chlorideand ethyl acetate as an eluant to provide 1.2 g. of oilyN-propyl-3-(2-pyridylmethylthio)propionamide.

Infrared absorption spectrum (cm⁻¹): 1640.

Nuclear magnetic resonance spectra (CDCl₃): δ: 0.88 (3H, t, J═7 Hz,NHCH₂ CH₂ CH₃), 1.49 (2H, m, NHCH₂ CH₂ CH₃), 2.44 (2H, t, J═7 Hz, CH₂SCH₂ CH₂ CO), 2.76 (2H, t, J═7 Hz, CH₂ SCH₂ CH₂ CO), 3.17 (2H, q, NHCH₂CH₂ CH₃), 3.83 (2H, s, CH₂ SCH₂ --).

Mass Spectrum: m/e 238(M⁺), 180.

EXAMPLE 47 ##STR71##

(a) In 50 ml. of dry tetrahydrofuran was suspended 7.5 g. of 50% sodiumhydride in oil in nitrogen gas stream and after adding gradually 16.6 g.of 2-mercaptoacetic acid methyl ester with stirring, they were reactedfor 30 minutes at room temperature. Then, a solution of 20 g. of2-chloromethylpyridine in 20 ml. of dry tetrahydrofuran was added to themixture below room temperature and stirring for 20 hours. Afterdistilling off the solvent under reduced pressure, the residue formedwas mixed with 70 ml. of water and extracted three times each time with100 ml. of ether. The ether layer was washed with water, dried overanhydrous magnesium sulfate, concentrated under reduced pressure, anddistilled under reduced pressure to provide 28.3 g. of2-pyridylmethylthio acetic acid methyl ester showing a boiling point of110°-114° C. (0.9 mm.Hg).

(b) In 40 ml. of a 40% methanol solution of methylamine was dissolved 5g. of 2-pyridylmethylthioacetic acid methyl ester and after allowing tostand the solution for 20 hours at room temperature, the reactionmixture was concentrated under reduced pressure and the residue waspurified by means of a silica gel column chromatography using a mixedsolvent of methylene chloride and ethyl acetate as an eluant to provide1.7 g. of oily N-methyl-2-(2-pyridylmethylthio)-acetamide.

Nuclear magnetic resonance spectra (CDCl₃): δ: 2.78 (3H, d, J═5 Hz,NHCH₃), 3.17 (2H, s, CH₂ SCH₂ CO), 3.85 (2H, s, CH₂ SCH₂ CO).

Mass Spectrum: m/e 196(M⁺), 138, 124.

EXAMPLE 48 ##STR72##

In 5 ml. of dry methanol was dissolved 3 g. of3-(2-pyridylmethylthio)-propionic acid methyl ester prepared accordingto Example 47-(a) and after adding thereto a solution of 78.0 mg. offree guanidine in 15 ml. of dry methanol, the mixture was allowed tostand for 24 hours. The crystals thus deposited were recrystallizedtwice each time with a mixture of ethanol and ether to provide 0.8 g. ofN-3-(2-pyridylmethylthio)propionylguanidine showing a melting point of149°-150.5° C.

Infrared absorption spectrum (cm⁻¹): 1660.

Nuclear magnetic resonance spectra (d₆ -DMSO): δ: 2.19 (2H, t, J═7 Hz,CH₂ CH₂ CO), 2.64 (2H, t, J═7 Hz, --SCH₂ CH₂ CO), 3.80 (2H, s, CH₂ SCH₂CH₂ CO).

EXAMPLE 49 ##STR73##

(a) To an ethanol solution of sodium ethoxide (i.e., a solution preparedby dissolving 1.6 g. of metallic sodium in 100 ml. of ethanol) was addeddropwise under ice-cooling a solution of 10 g. of2-chloromethyl-4-methylthiazole in 30 ml. of ethanol and the mixture wasstirred overnight at room temperature. Then, ethanol was distilled offfrom the reaction mixture under reduced pressure and the residue wasextracted three times each time with 100 ml. of ether. The ether extractwas dried over anhydrous potassium carbonate and the solvent wasdistilled off under reduced pressure to provide 12 g. of oily3-{(4-methylthiazol-2-yl)methylthio}propionitrile.

Mass spectrum: m/e 198.

(b) In a mixture of 36 ml. of chloroform and 4.2 ml. of ethanol wasdissolved 12 g. of 3-{(4-methylthiazol-2-yl)methylthio}propionitrile andafter passing 7 g. of a hydrogen chloride gas through the solution underice-cooling, the reaction mixture was maintained at 0°-5° C. for 8 days.The reaction mixture was poured in ice-water containing 50 g. ofpotassium carbonate and extracted three times each time with 100 ml. ofchloroform. The chloroform extract was dried over anhydrous potassiumcarbonate and then the solvent was distilled off under reduced pressureto provide 14.5 g. of oily ethyl3-{(4-methylthiazol-2-yl)methylthio}propionimidate.

(c) In 60 ml. of ethanol were dissolved 10 g. of ethyl3-{(4-methylthiazol-2-yl)methylthio}propionimidate and 1.9 g. ofcyanamide and the solution was allowed to stand overnight at roomtemperature. The reaction mixture was concentrated under reducedpressure and the residue was washed with ethyl acetate to provide 7.7 g.of N-cyano-3-{(4-methylthiazol-2-yl)-methylthio}propionamidine showing amelting point of 114°-115° C.

    ______________________________________                                        Elemental analysis for C.sub.9 H.sub.12 N.sub.4 S.sub.2 :                             C           H       N                                                 ______________________________________                                        Calculated:                                                                             44.98%        5.03%   23.31%                                        Found:    45.08%        4.96%   23.37%                                        ______________________________________                                    

EXAMPLE 50 ##STR74##

(a) In 100 ml. of an ethanol solution of sodium ethoxide (i.e., asolution prepared by dissolving 2.6 g. of metallic sodium in 100 ml. ofethanol) and after adding to the solution 11 g. of2-chloromethyl-4-methoxypyridine hydrochloride under cooling withice-water, the mixture was stirred overnight at room temperature. Thereaction mixture was concentrated under reduced pressure and the residuewas mixed with 100 ml. of water and extracted three times each time with100 ml. of ether. The ether extract was dried over anhydrous potassiumcarbonate and then the solvent was distilled off under reduced pressureto provide 10.5 g. of oily3-{(4-methoxypyridine-2-yl)methylthio}propionitrile.

(b) In a mixture of 30 ml. of chloroform and 3.5 ml. of ethanol wasdissolved 10.5 g. of 3-{(4-methoxypyridine-2-yl)methylthio}propionitrileand after passing 6 g. of a hydrogen chloride gas through the solutionunder cooling with ice-water, the solution was allowed to stand for 8days at 0°-5° C. The reaction mixture was poured in ice-water containing50 g. of potassium carbonate and extracted three times each time with100 ml. of chloroform. The chloroform extract was dried over anhydrouspotassium carbonate and then the solvent was distilled off under reducedpressure to provide 12 g. of oily ethyl3-(4-methoxypyridine-2-yl)methylthio propionimidate.

(c) In 70 ml. of ethanol were dissolved 12 g. of ethyl3-{(4-methoxypyridine-2-yl)methylthio}propionimidate and 2.2 g. ofcyanamide and the solution was allowed to stand overnight. The reactionmixture was concentrated under reduced pressure and the residue waspurified by means of a silica gel column chromatography using a mixedsolvent of chloroform and ethanol as an eluant to provide 11.5 g. of thecrystals of N-cyano-3{(4-methoxypyridine-2-yl)methylthio}propionamidineshowing a melting point of 132°-133° C.

    ______________________________________                                        Elemental analysis for C.sub.11 H.sub.14 N.sub.4 OS:                                  C           H       N                                                 ______________________________________                                        Calculated:                                                                             52.78%        5.64%   22.38%                                        Found:    52.59%        5.58%   22.46%                                        ______________________________________                                    

EXAMPLE 51

Medical composition: Tablets for oral administration.

Composition for 1,000 tablets:

    ______________________________________                                        N--Carbamoyl-3-(4-methyl-5-imidazolyl-                                        methylthio)propionamidine                                                                             200      g.                                           Starch                  37       g.                                           Milk sugar              50       g.                                           Magnesium stearate      3        g.                                           ______________________________________                                    

The above components were granulated using a starch paste as a binderand shaped into tablets of 9.5 mm. diameter by a conventional manner.

EXAMPLE 52

Medical composition: Formulation for injection.

Composition in 2 ml. of injection:

    ______________________________________                                        N--Carbamoyl-3-(4-methyl-5-imidazolyl-                                        methylthio)propionamidine.2HCl                                                                        260 mg.                                               Distilled water for injection                                                 (the Japan Pharmacopoeia) to make 2 ml.                                       ______________________________________                                    

The active component was dissolved in distilled water for injectionwhile passing therethrough a nitrogen gas and the solution was adjustedto a concentration of 13% (a concentration of 10% as base). The solutionwas filtered by a bacterial filter and 2.2 ml. of the solution waspoured in each 2 milliliter ampule in a sterilized state. Then, afterreplacing the space of the ampule with nitrogen gas, the ampule wassealed.

EXAMPLES 53-59

By following the same procedure as described in Examples 41-42, exceptfor differing starting materials, the following products were obtained.

EXAMPLE 53 ##STR75##

Reagent amine: H₂ NCN.

Melting point: 75°-83° C.

Recrystallization solvent: Ethanol-Ether.

Nuclear magnetic resonance spectra (DMSO-d₆): δ: 2.28 (3H, s, NHCH₃),2.5-2.9 (4H, m, --CH₂ CH₂ --), 3.64 (2H, s, --CH₂ --N<), 3.80 (2H, s,##STR76## 6.1-6.3 (2H, m, ##STR77##

Infrared absorption spectrum (KBr tab) cm⁻¹ : 2160.

EXAMPLE 54 ##STR78##

Reagent amine: H₂ NCN.

Nuclear magnetic resonance spectra (CDCl₃): δ: 1.08 (6H, t, --CH₂ CH₃),2.5-2.9 (8H, m, --CH₂ CH₃, --SCH₂ CH₂ --), 3.58 (2H, s, --CH₂ N<), 3.80(2H, s, ##STR79## 6.20 (2H, s, ##STR80##

Infrared absorption spectrum (neat cm⁻¹ : 2160.

EXAMPLE 55

    ______________________________________                                        Desired compound                                                               ##STR81##                                                                    NCyano-3-[5-(dimethylaminomethyl)thienylmethylthio]propion-                   amidine                                                                       Reagent amine                                                                 H.sub.2 NCN                                                                   Melting point                                                                 135-136° C.                                                            ______________________________________                                        Elemental analysis for C.sub.12 H.sub.18 N.sub.4 S.sub.2                                C (%)         H (%)   N (%)                                         ______________________________________                                        Calculated:                                                                             51.03         6.42    19.84                                         Found:    50.77         6.49    19.89                                         ______________________________________                                    

EXAMPLE 56 ##STR82##

Reagent amine: H₂ NCN.

Melting point: 102°-103° C.

Recrystallization solvent: Ethyl acetate.

    ______________________________________                                        Nuclear magnetic resonance spectra (DMSO-d.sub.6)                             ______________________________________                                        δ:                                                                                   ##STR83##                                                                     ##STR84##                                                                    2.5-2.8(4H, m, SCH.sub.2 CH.sub.2),                                            ##STR85##                                                                     ##STR86##                                                                     ##STR87##                                                        ______________________________________                                    

Infrared absorption spectrum (KBr tab) cm⁻¹ : 2160.

EXAMPLE 57 ##STR88##

Reagent amine: H₂ NCN.

    ______________________________________                                        Nuclear magnetic resonance spectra (CDCl.sub.3)                               ______________________________________                                        δ:                                                                               ##STR89##                                                                     ##STR90##                                                                     ##STR91##                                                                     ##STR92##                                                                     ##STR93##                                                            ______________________________________                                    

Infrared absorption spectrum (neat) cm⁻¹ : 2160.

EXAMPLE 58

    ______________________________________                                        Desired compound                                                               ##STR94##                                                                    NCyano-3-[5-N(2-hydroxyethyl)-Nmethylaminomethylfur-                          furylthio]-propionamidine                                                     Reagent amine                                                                 H.sub.2 NCN                                                                   Nuclear magnetic resonance spectra (CDCl.sub.3)                               δ:                                                                           ##STR95##                                                                     ##STR96##                                                                     ##STR97##                                                                     ##STR98##                                                                     ##STR99##                                                                     ##STR100##                                                                Infrared absorption spectrum (neat) cm.sup.-1 : 2160                         ______________________________________                                    

EXAMPLE 59

    ______________________________________                                        Desired compound                                                               ##STR101##                                                                   NCyano-3-[5-(dimethylaminomethyl)furfuryloxy]propionamidine                   Reagent amine                                                                 H.sub.2 NCN                                                                   Nuclear magnetic resonance spectra (CDCl.sub.3)                               δ:                                                                              ##STR102##                                                                    ##STR103##                                                                    ##STR104##                                                                    ##STR105##                                                            Infrared absorption spectrum (neat) cm.sup.-1 : 2160                          ______________________________________                                    

What is claimed is:
 1. A heterocyclic compounnd of the formula##STR106## wherein Het represents imidazolyl, either unsubstituted orsubstituted by halogen, hydroxyl, lower alkyl, lower alkoxy,hydroxymethyl, phenyl, benzyl, cyano, amino, aminoalkyl, amidinoalkyl; Zrepresents sulfur or oxygen; X represents the formula N--R₁ wherein R₁represents cyano, unsubstituted or lower alkyl-substituted carbamoyl,unsubstituted or lower-alkyl-substituted thiocarbamoyl; Y representsalkyl substituted by hydroxyl, amino or halogen, cycloalkyl of 3-6carbon atoms, lower alkenyl, lower alkynyl, aryl, unsubstituted orsubstituted by hydroxyl, amino or halogen, aralkyl, unsubstituted orsubstituted by hydroxyl, amino, or halogen, cyano, or carbamoyl; and mand n represent an integer of 1 to 3; or a pharmacologically acceptableacid addition salt thereof.
 2. A compound according to claim 1, which isN-2-propynyl-3-[(5-methylimidazol-4-yl)methylthio]-propionamidine andthe dihydrochloride salt thereof.
 3. A compound according to claim 1,which is N-carbamoyl-3-(4-methyl-5-imidazolylmethylthio)-propionamidine.4. A composition for inhibiting gastric acid secretion containing as theactive ingredient an effective amount of a heterocyclic compound ofclaim 1 and a pharmaceutically acceptable carrier.
 5. The compositionaccording to claim 4, wherein the active ingredient isN-2-propynyl-3-[(5-methylimidazol-4-yl)methylthio]-propionamidine or thedihydrochloride salt thereof.
 6. The composition according to claim 4,wherein the active ingredient isN-carbamoyl-3-(4-methyl-5-imidazolyl-methylthio)-propionamidine.
 7. Acomposition for oral administration as claimed in claim 4, containing asufficient amount of said compound to provide a dose of from 0.4 to 1 gper day when administered in 1 to 4 divided doses per day.
 8. A methodof inhibiting gastric acid secretion in a warm blooded animal whichcomprises administering an effective amount of the composition of claim4 to said warm blooded animal.
 9. The method as claimed in claim 8wherein said composition is administered orally in an amount varyingfrom 0.4 to 1 g each day.